CYCLOTEK PET RADIOPHARMACEUTICALS AUSTRALIA NEW ZEALAND. F18 PSMA imaging A viable option Dr Rob Ware

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1 CYCLOTEK PET RADIOPHARMACEUTICALS AUSTRALIA NEW ZEALAND F18 PSMA imaging A viable option Dr Rob Ware

2 Disclosure Clinical affiliation Peter MacCallum Cancer Centre I am a shareholder and Director of several CYCLOTEK companies whose prinicipal business is the commercial production of PET Radiopharmaceuticals in Australia and New Zealand

3 BACKGROUND Nuclear medicine long a main stay of prostate cancer management -bone scanning (WBBS) Status quo was shaken by advent of PSA screening Early detection raised hopes of cure, but exposed the inadequacies of cect and WBBS for staging/restaging and disease characteristion

4 BACKGROUND Problem of applying right treatment, to the right patient at the time persists Imaging remains crucial to the decision making process

5 BACKGROUND MRI improved primary assessment Advances have occurred in molecular imaging F18 Bone scan FDG can help identify bad players non invasively Choline PET/CT PSMA PET/CT

6 CHOLINE PET/CT evidence Systematic review indicates very good diagnostic performance Sensitivity Specificity Positive Likelihood ratio Negative Likelihood Ratio Staging Patient (N=637) 84% 79% 4.2 Lesion (N=5117) 66% 92% Re-staging Patient (N=1005) 85% 88% 7.2 Umbehr et al. European Association of Urology Peter Mac RCT evaluating independent and incremental value of FCHOL compared to CT/WBBS analysis awaited

7 CHOLINE PET/CT evidence Sensitivity limited, especially in patients with PSA< 2ng/ml. Surgically controlled studies have indicated per lesional sensitivity as low as 39%. Poor guide to grade of prostatic carcinoma False positives- inflammation

8 PSMA Biology Integral membrane carboxypeptidase II Expressed on % prostate cancers Function in tumour biology uncertain Increased expression higher grade, metastatic and castrate resistant tumours fold lower expression on normal cells except small intestine, renal tubular cells and salivary glands High expression also in renal cell carcinoma and tumour neovasculature

9 PSMA Biology Large number of agents developed Monoclonal antibodies In111-capromab recognised intracellular epitope and has limited sensitivity In111-J591 targets extracellular epitopes, accurately detects bone and soft tissue metastases Lu177-J591 has been used safely for therapy

10 PSMA Biology Large number of agents developed Monoclonal antibodies Small molecule inhibitors of catalytic site Tc I123/I124/I131 C11 Ga68 F18

11 Glutamate-Urea-Lysine based PSMA Ligands Pomper s JHU group have been leaders in the field of radiolabeled urea based PSMA inhibitors-first to report C11, I125, Ga68, and F18 labeled ligands based on GLU-urea- LYS Greater stability of HBED-CC (Eder et al) has led to Ga68 PSMA PET/CT ligand being introduced into many clinical imaging facilities world wide particularly Germany and Australia following early clinical reports in 2012

12 Ga68 HBED PSMA imaging PMCC performed over 700 studies since late 2014 Fast elimination of tracer from background tissues Highly sensitive and specific Ga68 PSMA-rising PSA after EBRT

13 Ga68 HBED PSMA imaging Site Analysed T/B mean T/B range Prostate Soft tissue Bone Ga68 PSMA-increasing PSA on ADT post RP

14 Ga68 HBED PSMA imaging

15 Ga68 HBED PSMA imaging Afshar-Oromieh et al. retrospectively investigated the diagnostic value of 68 Ga-HBED- PSMA-PET/CT in 319 patients with recurrent prostatic carcinoma PET/CT at 1 h p.i. detected PCa in 83% of the patients (264 of 319 patients) No false positive examinations Afshar-Oromieh et al. EJNMMI 2015

16 Ga68 HBED PSMA imaging Eiber et al. JNM 2015

17 Ga68 HBED PSMA vs FCHOL imaging Emmett et al. JNM 2016

18 Ga68 HBED PSMA vs FCHOL imaging Sensitivity PSA > 2ng/ml PSA.5-2ng/ml PSA <.5ng/ml PSMA 88% 71% 50% FCHOL 63% 36% 12% Total management impact 24/38. Major management impact in 13/38 patients due to Ga68 PSMA alone No additional management impact due to accurate discordant FCHOL findings

19 Ga68 HBED PSMA imaging Undoubtedly an excellent tracer for staging and restaging prostate cancer! Guide for planning and monitoring PSMA based radionuclide therapy On-site on demand production from a Ge/Ga generator Who could wish for more?

20 Ga68 HBED PSMA-some limitations? Logistical Staff resources for synthesis and quality control Variable generator synthesis yields Occasional generator failure Waste Low injected activity Limited image statistics/image noise Short half-life Late imaging difficult Cost staff Generator Kits Synthesis units Microbiology/endotoxin Compliant manufacturing environment Quality/Regulatory Milieu Generators not ARTG registered Complex synthesis -who is qualified to perform?

21 Ga68 PSMA alternatives Simpler synthesis Kit based formulation 0 min 30 min 60 min Ga68-THP-PSMA Phase 0/1 Trial PMCC

22 F18 PSMA development- F18 DCFBC 5 patients with prostate cancer studied (PSA 9-46) No adverse effects Radiation dose similar to FDG Slow blood clearance 21 known metastatic lesions visualised 11 sites (bone>soft tissue) visualised, presumed metastases Lesion contrast less than typically seen with Ga68HBED Cho et al. JNM 2012

23 F18 PSMA development- F18 DCFBC 13 patients with primary prostate cancer studied Compared PET/CT, MRI and surgical pathology on a dominant lesion basis Sensitivity PET.46 vs MRI.92 All Gleason 8 and 9 score lesions >1cc volume detected by PET Low contrast apparent Cho et al. JNM 2015

24 F18 PSMA development- F18 DCFPyL Phase O/1 Trial data Safe favorable biodistribution favorable dosimetry Szabo et al. JNM 2015

25 F18 PSMA development- F18 DCFPyL Phase O/1 Trial data High uptake in prostate carcinoma lesions More lesions apparent with time Excellent image qaulity Szabo et al. JNM 2015

26 F18 PSMA development- F18 DCFPyL Phase O/1 Trial data Different time course of uptake in primary, node and bone metastases Possibility of greater sensitivity at later time points than feasible with Ga68 PSMA Szabo et al. JNM 2015

27 F18 DCFPyL vs Ga68HBED PET/CT Direct comparison F18DCFPyL and Ga68HBED 14 patients relapsed prostatic carcinoma (PSA.4-50 ng/ml Administered activity of F18 at least 1.5 x Ga68 F18DCFPyl Ga68HBED Dietlein et al. Mol Imaging Biol (2015)

28 F18 DCFPyL vs Ga68HBED PET/CT SUV values higher for F18 DCFPyL vs 12.2, p=.028 T/B F18 DCFPyL Higher kidney, spleen, parotid Same liver, mediastinum Dietlein et al. Mol Imaging Biol (2015)

29 F18 DCFPyL vs Ga68HBED PET/CT All Ga68HBED lesions visualised on F18DFFPyL 3 patienst additional lesions F18DCFPyL had potential management indications F18DCFPyl Ga68HBED Dietlein et al. Mol Imaging Biol (2015)

30 F18 DCFPyL vs Ga68HBED PET/CT F18 DCFPyL synthesis High radiochemical purity (>95%) Both excellent tracers F18DCFPyL appears to provide better image quality Higher injected dose Later imaging time Less energetic positron emission diagnostic performance appears non inferior High specific activity (mean GBq/micromole) Low yield (3 12 % non decay corrected) Complex two reactor synthesis Long synthesis of 90 minutes or more Synthesis characteristics make commercial distribution problematic

31 Recent improvements to F18 DCFPyL production Bouvet et al reported (SNM 2015) a simplified F18 DCFPyL synthesis Radiochemical yield after HPLC of 27% decay corrected 45 minute synthesis duration Automated Similar results achieved at Johns Hopkins and by ABX Good basis for cost effective centralised production and distribution of F18PSMA ligand

32 CYCLOTEK develoment path Begin production validation for GMP compliance Do local non inferiority trial and Peter Mac Facilitate multi-centre trials to establish improved clinical and economic outcomes Make available for individual patient use in Australia and New Zealnd

33 CONCLUSION PSMA imaging with PET/CT is a huge advance for diagnostic assessment of patients with primary and recurrent prostatic cancer F18 PSMA imaging appears viable with DCFPyL, a GuL small molecule inhibitor developed at John s Hopkins and which has been licensed to CYCLOTEK for clinical trial and clinical use in Australia and New Zealand Non inferior diagnostic performance to Ga68 HBED demonstrated Logistic improvements appear likely with development of improved and automated synthesis Cost efficiencies should be achievable GMP production will impact potential quality and regulatory issues associated with Ga68 HDEB, and may impact reimbursement potential

34 Register Early The 4 th Theranostics World Congress (4TWC) November 7 9,